tbuckley/cabot-search huggingface dataset:
Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: Evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications.
Authors: Alexandre Akoulitchev, Ewan Hunter, Francisco C. Santos, Mehrnoush Dezfouli, Christina Koutsothanasi, Matthew Salter, Ryan Powell, Ann Dring, Benedict Egan, Matthew Parnall, Morgan Thacker, Jayne Green, Aroul Ramadass, Serene Ng, Chun Ren Lim, Thomas Guiel, Robert Heaton, Jedd Levine
Journal: Journal of Clinical Oncology (2022)

e14525 Background: Unprecedented advantages in cancer treatments with immune checkpoint inhibitors (ICI) remain limited to a subset of patients, with high demands for development of better biomarkers to access likely clinical response in advance of ICI therapeutic interventions. 3D genomics has emerged as a novel molecular biomarker modality with strong functional correlation to clinical outcomes (1). The last few years have seen rapid emergence of 3D genomics applications in clinical stratifications. They have demonstrated high sensitivity and specificity in patient stratifications, offered solutions in symptomatic and pre-symptomatic diagnosis, in prognosis, residual disease monitoring, and prediction of response to therapeutic interventions (2-8). EpiSwitch is a 3D genomic platform that has been reduced to practice for the discovery of 3D genomic blood-based biomarkers in a variety of immune-related and oncological diseases (7,8). Methods: A clinical blood assay based on 8 markers - Checkpoint Inhibitor Response Test (CiRT) - has been developed to predict response to PD-(L)1 immune checkpoint inhibition from over 30 million data points, with validations on several independent cancer patient cohorts. The predictive 8 biomarker set is based on an observational clinical trial and several retrospective cohorts, representing all together 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in over 15 diverse oncological indications, i.e. melanoma, lung, urethral, hepatocellular, bladder, prostate, head and neck, colon, breast, bone, brain, lymphoma, larynx. Results: CiRT has demonstrated high accuracy up to 85%, sensitivity of 93% and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach could be successfully utilized for development of a non-invasive predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients. CiRT can assist in treatment decisions, help improve patient selection for optimized treatment, utilize alternative effective treatments, minimize unnecessary toxicity, and efficiently manage the costs.
Race/ethnicity and outcomes in hematopoietic stem cell transplantation (HCT) in myeloproliferative neoplasms (MPN): A single institutional study.
Authors: Snegha Ananth, Paul Shaughnessy, Behyar Zoghi, Jonathan Gelfond, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2022)

e19083 Background: Previous studies have demonstrated racial disparities in MPN outcomes, but there is no data regarding impact of race on outcomes of HCT in MPN. This is a retrospective study evaluating transplant related outcomes in Hispanics undergoing allogeneic HCT for MPN/MF in a large hospital in South Texas. Methods: A total of 45 patients who underwent HCT for MPN disorders from January 2008 to December 2020 at the Methodist Hospital, San Antonio were included. Race was self-reported by patients and obtained from electronic medical record along with other variables. Significance of variation in categorical outcomes were assessed with Chi-square tests. OS was estimated using the Kaplan-Meier method and compared between races using the log rank test. Results: This study analyzed 19 Non-Hispanic White (NHW) and 19 Hispanic (H) patients (7 patients were excluded due to unknown or other race). Patients primarily underwent transplantation for Myelofibrosis (n=19) followed by CMML (n=12) and MDS-MPN-U (n=7). There were no significant differences between NHW and H patients with regards to performance status, conditioning regimen, stem cell source and GvHD prophylaxis. However, H were younger at transplant with a median of 52 years (range 42-71) compared with 62 years (41-76) in NHW (p=0.50) and were more likely to have a haploidentical donor (47% vs 11%, p &lt; 0.001). There were no significant differences in time to neutrophil (median 22 days (range 15-560) versus 25 days (range 8-48 days), p=0.7) or platelet recovery (median 24 days (range 15-636) versus 25 days (range 6-102), p=0.9) in NHW vs H patients. There were no significant differences in cumulative incidence of grade 1-2 and grade 3-4 acute GvHD between NHW (50 and 50%) vs H (40 and 60%) patients (p=0.4 and p=0.5, respectively). There was significant difference in the cumulative incidence of chronic GvHD (68% NHW compared to 37% H, p=0.03). Median OS was 6.75 years in NHW and 2.67 years in H (p=0.08). The cumulative incidence of Relapse Mortality (RM) and non-RM were not statistically significant between NHW and H, however H had higher percentage of relapse related mortality at 5 years (5.3% vs 17.5%)(Table). Among the 5 NHW and 8 H non-relapse deaths, causes of death were similar among the two groups – the most common being infection (20% and 38%, respectively), acute and chronic (40% and 25%) GvHD and graft failure (0% and 25%). Conclusions: NHW and H had comparable relapse, non-relapse and survival rates likely due to similar access to treatment and follow-up within a single institution. Larger and prospective studies are needed to further elucidate this important topic.[Table: see text]
Longitudinal sequencing of T cell receptor revealed radiotherapeutic efficacy and prognosis in non-small cell lung cancer patients with brain metastasis.
Authors: Xiaorong Dong, Fan Tong, Hao Zeng
Journal: Journal of Clinical Oncology (2022)

e21056 Background: Liquid biopsy has played a unique role in long-term surveillance of brain metastasis in non-small cell lung cancer (NSCLC), due to the inaccessibility of solid metastatic biopsies. T cell-mediated immunity is critical in the oncogenesis and metastasis of NSCLC, and sequencing in T cell receptor (TCR) provides a robust method to quantify T cell diversity. Therefore, we aimed to explore the alteration of TCR through liquid biopsy before and after radiotherapy of NSCLC brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. Cerebrospinal fluid (CSF) and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. TCR sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate TCR signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.
A secondary data analysis of colorectal cancer screening among males assigned at birth: Differences by sexual orientation and race/ethnicity.
Authors: Hui Xie, Yannan Li, Haoxin Le, Qian Wang, Nicholas Theodoropoulos, Chi Wen
Journal: Journal of Clinical Oncology (2022)

3529 Background: We have limited information on CRC screening disparities in people of color (POC) with sexual minority identity. Methods: We analyzed the Behavioral Risk Factor Surveillance Survey (BRFSS) data of males assigned at birth age 50-75 years for up-to-date CRC screening. Descriptive analyses in demographics, socioeconomics, healthy behaviors, and CRC screening were conducted by race/ethnicity, followed by multivariable regressions to identify predictors of CRC screening stratified by race/ethnicity. Results: About 67.70% of eligible males reported having an up-to-date CRC screening that met the USPSTF guideline, with the highest rate among gay men (74.92%) and the lowest among bisexual men (65.35%; p = 0.0024). Non-Hispanic Whites had the higher rates of receiving CRC screening across all groups (p &lt; 0.010). In the adjusted multivariable logistic models for NH-White males, gay men (1.52, 95% CI: 1.20-1.91), non-current smokers (1.56, 95% CI: 1.44-1.69), being overweight/obese (1.15, 95%CI: 1.07-1.23), and being physically active (1.08, 95%CI: 1.00-1.16) had greater odds of having CRC screening. Similar patterns were not found in Hispanic and non-Hispanic Black males. Gay men (3.88, 95% CI: 1.51-9.98) had greater odds of CRC screening in Hispanics, whereas being a non-current smoker (1.42, 95%CI: 1.13-1.79) was a significant factor in NH-Blacks. Health insurance coverage was a significant factor across all racial/ethnic groups. Conclusions: CRC screening disparities were most pronounced among racial/ethnic minority males. Future work on developing tailored CRC screening programs for racial/ethnic subgroups using an intersectional framework is warranted to elucidate observed heterogeneity across race/ethnicity and sexual orientation.
Utilization of nano-hmC-seal technology to detect epigenetic signatures of peritoneal metastasis in cell-free DNA (cfDNA) in patients with colorectal and high-grade appendiceal cancer.
Authors: Ankit Dhiman, Yuri Malina, Lu Gao, Diana West-Szymanski, Marco Rivas, Xiao-Long Cui, Hunter D. D. Witmer, Yaniv Berger, Leah Ulrich, Urszula Dougherty, Akushika Kwesi, Wei Zhang, Chuan He, Marc Bissonnette, Kiran Turaga
Journal: Journal of Clinical Oncology (2022)

e15510 Background: Peritoneal metastases from lower GI tumors are common and cause significant morbidity. Assays of circulating-tumor DNA (ctDNA) to identify peritoneal recurrence after curative-surgical intent are limited due to the low abundance of DNA shed by these tumors, especially mucinous tumors. We demonstrate for the first time an ultra-sensitive test to detect biomarkers modified by the epigenetic mark 5-hydroxymethylcytosine (5hmC) in human cfDNA utilizing nano-hmC seal technology to identify patients with peritoneal metastases (PM) after curative-intent resection. Methods: Patients treated with curative intent resection of colorectal (CRC) and high-grade appendiceal (HGA) cancers underwent prospective plasma collection. Peritoneal disease was documented by direct visual inspection (laparoscopy/laparotomy). Plasma samples were analysed using nano-hmC-seal technique to obtain 5hmC signatures. Genome-wide differential analysis was used to identify significant 5hmC- differentially modified gene body regions (p-value &lt; 0.01 and log-fold change &gt; 10%). Functional annotation analysis was performed to further characterize differentially 5hmC -modified genes noted on multivariate logistic models. Results: Of 64 patients included in the study (CRC = 26; HGA = 38), 47 (73%) were PM+. The median DNA extracted per sample was 23.5 ng (IQR: 15.8-38.3), and no sample failed sequencing criteria. After genome-wide analysis, 39 gene body regions were identified as differentially 5hmC-modified, and 14 genes remained significant after multivariate adjustment. The signatures for PM+ patients were distinguishable from PM- patients using hierarchical clustering and principal component analyses. Functional annotation analysis based on the 14 genes point to alterations in immune and microbiome-related pathways in PM+ group (Table). Conclusions: We report for the first time the detection of peritoneal metastasis in cfDNA from human lower GI cancers using nano-5hmC seal epigenomic technology. This technology could be exploited to detect recurrences in tumors that shed very low levels of cfDNA. This signature is being validated in a prospective clinical trial (NCT 04157322).[Table: see text]
Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.
Authors: Qiaxuan Li, HaiYu Zhou
Journal: Journal of Clinical Oncology (2022)

3140 Background: As a key regulator of programmed cell death, autophagy is critical for maintaining the stability of the intracellular environment. Increasing evidences have found that the clinical importance of the interaction between autophagy and immune status in LUAD. Reliable prognostic signatures based on combination of autophagy and immune status have not been well-established. We aimed to explore the potential autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in lung adenocarcinoma. Methods: Patients from GSE72094 dataset were randomized 7:3 to a training set or an internal validation set. Three independent cohorts, TCGA, GSE31210 and GSE37745, were used as the external verification. Unsupervised hierarchical clustering was used to identify the autophagy-associated and immune-associated molecular patterns for LUAD based on autophagy-genes and immune-genes. The LASSO analysis, univariate and multivariate cox regression analysis were performed to filtrate significant prognostic autophagy-immune-based genes, followed with model construction and patient stratification. Tumor immune microenvironment and functional pathways were investigated. The potential therapeutic responses were explored by GDSC database, TIDE algorithm, and immunotherapy clinical cohorts. Results: We found that autophagy cluster A had the better survival prognosis (p &lt; 0.001) and high immune status (p &lt; 0.001) was identified as favorable factors for patients’ overall survival. We merged autophagy and immune subtype into a two-dimensional index to characterize the combined prognostic classifier 535 genes were defined as autophagy-immune-related DEGs. Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct the autophagy-immune-related prognostic risk model. Survival analysis and receiver operating characteristic curve showed significant prognostic efficacy. Through ssGSEA and CIBERSORT analysis, the majority of immune infiltrating cells were shown to be enriched in the low-risk group. What’s more, the expression of crucial immune checkpoint molecules, such as PD-1, PD-L1 and CTLA-4, was observed highest in low-risk group (p &lt; 0.001). TIDE and immunotherapy clinical cohorts’ analysis showed that low-risk group was predicted with more potential responders to immunotherapy. In addition, there are different patterns of autophagy between low- and high- risk patients. GO, KEGG and GSEA function analysis focus on cell cycle, MAPK, apoptosis, MTORC1 and selective autophagy pathway. Docetaxel, rapamycin and sorafenib may be the potential drugs candidate in high-risk group (p &lt; 0.01). Conclusions: In summary, the autophagy-immune-based gene signature represents a promising tool for risk stratification tool in lung adenocarcinoma, which can regard individualized treatment and follow-up scheduling for patients.
Time-of-day infusion of immunotherapy may impact outcomes in advanced non-small cell lung cancer patients (NSCLC).
Authors: Carlos H. Barrios, Tatiane Caldas Montella, Carlos G. M. Ferreira, Pedro De Marchi, Luiz Flavio Coutinho, Igor Lemos Duarte, Matheus Costa e Silva, Rafael Duarte Paes, Guilherme Munhoz Correia e Silva, Rodrigo Dienstmann
Journal: Journal of Clinical Oncology (2022)

e21126 Background: Circadian rhythms have shown direct impact on toxicity and efficacy of anticancer treatments. Adaptive immune responses related to (or associated with) check point inhibitor (CPI) administration may have lower intensity later in the day. Notably, emerging evidence suggests that the time-of-day administration of different immunotherapies could have survival implications in different tumor types. Methods: We extracted de-identified data from curated the Real-World database of the Oncoclínicas Group, including 21 community-oncology practices in Brazil with EHR information on time-of-day administration of CPI in patients with advanced NSCLC. Only patients treated with single-agent CPIs with palliative intent (Nivolumab, Pembrolizumab or Atezolizumab) from Jan 2018 through Dec 2021 were analyzed. The primary endpoint was a comparative analysis of the median Time to Treatment Discontinuation (TTD) of CPI stratified according to time-of-day administration using a propensity-score (PS) matching model. On the basis of previous reports, we selected the cutoff of 20% of CPI doses administered after 4:00 pm as the late-day subgroup. Variables included in PS matching were: age (&lt; 60, 60+); line of therapy (1 st , 2 nd or beyond); gender (male, female), and CPI agent (Pembrolizumab vs. others). Results: From a total of 1,603 patients with advanced NSCLC treated at Oncoclínicas during the study period, 508 received CPI as per inclusion criteria. Median age was 73 years (36-94), 66% were male, 63% received CPI in the 1 st line setting, 50% with Pembrolizumab. Overall, 219 CPI infusions (15%) occurred after 4:00 pm and 9% of the patients (n = 43) qualified as late-day infusion subgroup (more than 20% of infusions after 4pm). Median TTD was 4.9 months (CI 95%, 2.83-13.5) in these patients. In the PS matched population with early-day infusions (2:1, n = 86), median TTD was 14 months (CI 95%, 8.87-23.4). Overall, with 73 events in 129 patients, we found a significantly increased risk of treatment discontinuation in the late-day subgroup (HR 1.61, CI95% 1.0-2.6, p = 0.05). With only 33 death events and median follow-up of 11 months, median overall survival was not reached in late-day or early-day subgroups (HR 1.25, CI95% 0.6-2.6, p = 0.5). Conclusions: This preliminary and exploratory real-world data analysis suggests that the time-of-day administration of CPI in patients with advanced NSCLC could have a meaningful impact on patient outcomes, in line with studies conducted in melanoma. This simple and inexpensive intervention merits further exploration in prospective controlled clinical trials.
Prediction of immunotherapy response by integrating immune infiltration and neoantigen presentation score in late-stage melanoma.
Authors: Bailiang Li, Charles Abbott, Lee McDaniel, Rachel Marty Pyke, Fabio Navarro, Hima Anbunathan, Gabor Bartha, Jason Harris, Michael Snyder, Sekwon Jang, Sean Michael Boyle, Richard Chen
Journal: Journal of Clinical Oncology (2022)

e21554 Background: Single modality biomarkers such as tumor mutational burden (TMB) fail to reliably predict response to immune checkpoint blockade (ICB) in part due to their incomplete characterization of complex tumor-immune interactions impacting response. We previously developed the composite biomarker, neoantigen presentation score (NEOPS TM ), which integrates neoantigen processing and presentation information and showed it outperformed TMB and other single analyte biomarkers in predicting response in melanoma. Here we combined NEOPS with tumor immune infiltration analysis, and demonstrated further improved patient stratification for ICB response. Methods: We assessed the effect of 17 different immune and stromal cells on NEOPS using logistic regression with interactions in a retrospective cohort of 45 stage III/IV melanoma patients who underwent anti-PD-1 therapy. NEOPS and immune cell infiltration status were both generated using Personalis’ ImmunoID NeXT Platform ® . The identified immune-selected phenotype that had a significant effect on NEOPS performance was validated in a cohort of 109 anti-PD1 treated late-stage melanoma patients. Results: The predictive strength of NEOPS was enhanced by considering the infiltration status of 4 distinct immune cell types derived from expression signatures: naïve CD4/CD8 T, exhausted CD8 T, and CD8 T cells. Highly correlated cells were aggregated into naïve (naïve CD4/8 T) and CD8 (exhausted and CD8 T) features. Both features independently boosted the accuracy of NEOPS in the validation cohort (naïve: P int. = 0.048; CD8: P int. = 0.11). In immune-selected patients in the validation cohort displaying both high naïve and CD8 features, NEOPS achieved an improved accuracy of 77.2% (vs 69.7% baseline performance, P = 0.013) and an AUC of 0.74 (vs 0.66, P = 0.055). In anti-CTLA4 treatment naïve patients, the immune-selected group attained even better NEOPS performance, with an accuracy of 81.8% (vs 70.6%, P = 0.015) and an AUC of 0.89 (vs 0.68, P = 0.005) in the validation cohort. A separate approach integrating NEOPS with naïve and CD8 features into a single composite biomarker resulted in an AUC of 0.82 (cross validation: 0.78 vs 0.71 baseline). Conclusions: Stratifying immune-selected patients based on cellular composition of the tumor microenvironment significantly increased the accuracy of our neoantigen-based biomarker of ICB response, NEOPS. These data highlight the potential for combining tumor microenvironment information with neoantigen analysis into a composite biomarker to provide more sensitive prediction of immunotherapy response.[Table: see text]
A biomarker-guided Bayesian response-adaptive phase II trial for metastatic melanoma: The Personalized Immunotherapy Platform (PIP) trial design.
Authors: Serigne N. Lo, Tuba Nur Gide, Maria Gonzalez, Ines Silva, Alexander M. Menzies, Matteo S. Carlino, Richard A. Scolyer, Stephane Heritier, James S. Wilmott, Georgina V. Long
Journal: Journal of Clinical Oncology (2022)

TPS9599 Background: Anti-PD1-based immunotherapies have been approved for many cancer types and are now a standard therapy for advanced melanoma. Despite this, ̃50% of advanced melanoma patients (pts) fail to respond or eventually progress after response. It is therefore critical to identify pts with a low likelihood of response to anti-PD1-based therapy and efficiently assess activity of rationally-selected alternative novel immunotherapies. Methods: We designed this investigator-initiated phase II PIP-Trial to evaluate two consecutive biomarker testing platforms, followed by the activity of rationally selected 5 novel agents in pts with advanced melanoma. Two separate pt populations are included: Part-A) treatment-naïve pts predicted to be resistant to either anti-PD-1 alone or combined with ipilimumab using Biomarker Test-1); and Part-B) pts who had progressed on 1 prior line of PD1-based therapy. Part-A) is a Bayesian adaptive multi-arm multi-stage design using response adaptive randomisation after a burn-in period where pts are randomised to the existing arms with equal probability. From then on, regular interim analyses will be carried out with the objective to either drop poorly performing arms or continue. Part-B) is an open platform without control that combined a selection and an expansion phase to identify best novel agent(s) as second-line therapy. Expansion phase decisions will be based on enrichment for biomarker Test-2. Dropping an arm occurs when the posterior probability of observing a clinically significant effect on the primary outcome (i.e. 6-month RECIST objective response rate (ORR)) is low. The operational characteristics of the design were investigated through simulations considering 4 plausible scenarios with 40% ORR in the control arm (anti-PD1 + Anti-CTLA4). Simulations were based on the upcoming R package BATS. Part-A has at least 85% power to detect a 30% absolute improvement in ORR with respect to the control arm (with a max N = 216 – Table below). Part-B will be able to select two promising treatments in the expansion phase and formally test their efficacy against a minimum ORR of 25% at 80% power (max N = 150). [Table: see text]